New study identifies mechanisms of resistance against targeted immunotherapy in multiple myeloma

Cancer therapies that harness the immune system to fight tumours — called immunotherapies — are becoming increasingly common, especially in blood cancers where they tend to be particularly effective. 

While immunotherapies work exceptionally well for some patients, many tumours unfortunately develop resistance to them, causing patients to relapse. 

In a new study published in the prestigious journal Nature Medicine, a team of researchers funded in large part by the Marathon of Hope Cancer Centres Network investigated how tumours develop resistance to a specific type of immunotherapy targeted to a molecule called GPRC5D. 

The team, led by Drs Holly Lee, Paola Neri and Nizar Bahlis at the University of Calgary, performed whole-genome sequencing and other molecular profiling on tumours from 21 multiple myeloma patients who relapsed following anti-GPRC5D therapy. 

They found that tumours evolved in different ways to evade the therapy — including, sometimes, multiple ways within the same tumour. 

The study specifically looked at patients who received a category of immunotherapy called T cell-engager (TCE) therapy. These drugs are composed of molecules with two domains: one that binds to a target found on cancer cells, and another that binds to a type of immune cell called a T cell that can kill tumour cells. TCE molecules thus work by effectively bringing T cells directly to tumour cells. 

Since TCE therapy relies on the drug molecule physically binding to a molecule found on the surface of cancer cells (in this case, GPRC5D), tumours can evolve to either no longer produce that surface molecule, or to produce a version of it that is not recognized by the drug. 

This is what the team found was happening in most cases, although through different means.  

In some relapsed tumours, the GPRC5D gene was deleted from the genome entirely, meaning that those cells no longer produced the molecule for the drug to bind to. In other cases, the GPRC5D gene was silenced epigenetically — a process that does not include physical changes to the DNA like a deletion, but that causes the molecule to no longer be produced nonetheless.  

In yet other cases, the team found mutations in the GPRC5D gene that caused the molecule to no longer be recognized by the drug. Some mutations also caused GPRC5D to no longer be shuttled to the cell surface as it normally is, keeping it ‘hidden’ from the drug inside the cell. 

“Understanding the different mechanisms tumour cells use to evade treatment gives clinicians a clearer blueprint for which patients are likely to respond to a treatment and who is at higher risk of relapse,” says lead author Dr. Holly Lee. “It also opens the door to creating next-generation TCE therapies or combinations of drugs that can block or bypass these escape strategies.” 

The team also found that some tumours had more than one of these kinds of alterations, suggesting that different clones within the tumour can develop resistance through different methods. This is especially important because it means that a multi-pronged approach may be needed to overcome resistance. 

“This work would not have been possible without support from the Marathon of Hope Cancer Centres Network and, through integrated genomic, transcriptomic, and epigenomic analysis, demonstrates the value of the Network’s mission to advance data-driven precision oncology,” highlights Dr. Bahlis. 

By identifying mechanisms of treatment resistance, this study will help inform new research and clinical trials to find ways of overcoming this resistance, leading to better outcomes and quality of life for patients with multiple myeloma — and perhaps more broadly as well. 

“We are building the frameworks needed for precision immunotherapy,” says Dr. Neri. “This will help us reach more durable responses with personalized immune-based therapies that anticipate tumour evolution and that are designed to overcome or even prevent resistance.”